The present invention relates to a drug complex in which a drug carrier such as polysaccharide derivatives and a drug compound such as antineoplastic agents are bound to each other via a spacer.
Antineoplastic agents, used for treatment of solid cancers such as lung cancer or digestive organ carcinomas and blood cancers such as leukemia, are systemically administered through routes of administration such as intravenous or oral administration, and then, are distributed to certain tumorous sites and inhibit or suppress the proliferation of cancer cells to exhibit their therapeutic efficacy. However, the systemically-administered antineoplastic agents are rapidly taken into livers and reticuloendothelial organs from blood, or rapidly excreted into urine, and accordingly, their blood concentrations may sometimes be lowered to render the distribution into tumorous sites insufficient. In addition, antineoplastic agents ordinarily used have poor distribution selectivity to tumorous sites (tumor selectivity), and therefore, the antineoplastic agents are uniformly distributed over various tissues and cells of the whole body and act as cytotoxins also against normal cells and tissues, which results in problems of the appearance of adverse effects, e.g., emesis, pyrexia, or alopecia at an extremely high rate. Therefore, it has been desired to develop antineoplastic agents which distribute efficiently and selectively to tumorous sites.
As one of such means, a process was proposed in which a polysaccharide derivative having carboxyl groups is used as a drug carrier, and an antineoplastic agent is bound to the polysaccharide derivative to delay the disappearance of the antineoplastic agent from blood and to enhance selectivity to tumor tissues. For example, International Publication WO94/19376 discloses a drug complex in which a peptide chain (the number of amino acid residues: 1 to 8) is bound to a carboxyl group of a polysaccharide having carboxyl groups, and doxorubicin, daunorubicin, mitomycin C, bleomycin or the like is further bound by means of the peptide chain. In addition, Japanese Patent Publication (KOKOKU) No. (Hei) 7-84481/1995 discloses a drug complex in which the aforementioned antineoplastic agent is introduced into a carboxymethylated mannoglucan derivative using a Schiff base or an acid amide bond. These drug complexes have more excellent antineoplastic activity, and reduced toxicity and adverse effects compared to antineoplastic agents, per se, that are bound to drug carriers.
There are some reports relating to drug complexes utilizing polyalcoholized polysaccharide derivatives as drug carriers, for example, xe2x80x9cResearches on polysaccharide-peptide-doxorubicin complexesxe2x80x94Correlations between stabilities of polysaccharide carriers in blood and their antineoplastic activitiesxe2x80x9d Abstracts of 10th Meeting of the Japan Society of Drug Delivery System, 279, 1994); xe2x80x9cResearches on polysaccharide-peptide-doxorubicin complexesxe2x80x94Pharmacokinetics and antineoplastic activityxe2x80x9d (Abstracts of 9th Annual Meeting of Japanese Society for the study of xenobiotics, 292, 1994); Abstracts of 19th Seminar of Trends in Research and Development (held by the organization for Pharmaceutical Safety and Research), D-9, 1995; and xe2x80x9cResearches on drug delivery to a tumor tissue by polysaccharide carriersxe2x80x9d (Abstracts of 12th Colloid and Interface Technology Symposium, The Chemical Society of Japan, 51, 1995). In addition, reagents comprising p-aminobenzyloxycarbonyl group and peptide group were developed as a technology for binding antineoplastic agents to antibodies and the like (Dubowchik, G. M., Tetrahedron Lett., 38, 5257, 5261, 1997). However, application to drug complexes having drug carriers as described above has not been known.
The inventors of the present invention made intensive studies on drug complexes in which a drug carrier such as polysaccharide derivatives and a drug compound such as antineoplastic agents are bound to each other via a spacer comprising 1 to 8 amino acids, thereby successfully providing a drug complex which can site-selectively distribute the drug compound such as antineoplastic agents to target tissues (International Publication WO97/46260). However, the inventors found that a releasing rate of a drug compound from a drug complex, which comprises a spacer comprising 1 to 8 amino acids, is occasionally independent of the rate of enzymatic degradation (hydrolysis by peptidase) of the spacer moiety, and the releasing rate may sometimes be affected by the steric structure of the drug compound. Especially where the binding moiety between the reactive functional group (e.g., amino group) of the drug compound and the spacer has steric hindrance, the tendency was found to be highly remarkable. In addition, when such drug complexes are used, drug compounds are sometimes released by enzymatic degradation of the spacer which have one or a few residual amino acids derived from the spacer, thereby irregular release of the drug compound is sometimes caused.
Accordingly, an object of the present invention is to provide a drug complex formed by binding a drug compound such as antineoplastic agents and antiinflammatory agents to a drug carrier via a spacer comprising 1 to 8 amino acids, which can site-selectively distribute the active ingredient to tumorous sites and the like and in which the releasing rate of the drug compound substantially depends on the rate of enzymatic degradation of the spacer moiety. In addition, another object of the present invention is to provide a drug complex in which the releasing rate or the drug compound is not substantially affected by the steric structure of the drug compound, and a releasing rate of the drug compound can be achieved which is expected from the rate of enzymatic degradation of the spacer moiety.
The inventors of the present invention made intensive studies to achieve the aforementioned objects. As a result, they found that, in drug complexes formed by binding a drug compound such as antineoplastic agents and anti-inflammatory agents to a drug carrier via a spacer comprising 1 to 8 amino acids, further insertion of aminobenzyloxycarbonyl group and the like between the spacer and the drug compound causes immediate non-enzymatic hydrolysis of the aminobenzyloxycarbonyl group after enzymatic hydrolysis of the spacer moiety to release the drug compound. They also found that, in the aforementioned drug complex, the releasing rate of the drug compound is not affected by the steric structure of the drug compound and substantially depends on the rate of enzymatic degradation of the spacer moiety. The present invention was achieved on the basis of these findings. The drug complex of the present invention is characterized in that the releasing rate of the drug 3% compound can be controlled on the basis of the rate of enzymatic degradation of the spacer moiety, regardless of the steric structure of the drug compound.
The present invention thus provides a drug complex represented by the following formula (I):
A-Rxe2x80x94NHxe2x80x94Yxe2x80x94CH2xe2x80x94Oxe2x80x94CO-Q 
wherein A is a polymer as a drug carrier; R is a spacer, wherein said spacer is an amino acid or an oligopeptide comprising 2 to 8 amino acids; Y is phenylene group which may be substituted; and Q is a residue of a drug compound. The drug complex is useful, for example, as a DDS (drug delivery system) compound having the DDS function.
According to another aspect of the present invention, we, inventors, found a compound represented by the following formula: Rxe2x80x2xe2x80x94NHxe2x80x94Yxe2x80x94CH2Oxe2x80x94CO-Q, wherein Rxe2x80x2xe2x80x94 is a group which comprises one amino acid or peptide-bonded 2 to 8 amino acids and of which N-terminal is protected or not protected; Y is phenylene group which may be substituted; and Q is a residue of a drug compound; and a compound represented by the following formula: A-Rxe2x80x94NHxe2x80x94Yxe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94X, wherein A is a polymer as a drug carrier; R is a spacer, wherein said spacer is an amino acid or au oligopeptide comprising 2 to 8 amino acids; Y is phenylene group which may be substituted; and X is selected from the group comprising hydroxyl group, xe2x80x94O-M wherein M is a protective group for carboxyl group, or an eliminating group. These compounds are useful as synthetic intermediates for the manufacture of the aforementioned drug complex.
According to preferred embodiments of the present invention, we found the above drug complex wherein the drug carrier is a polysaccharide derivative having carboxyl groups; the above drug complex wherein R is a spacer comprising peptide-bonded 2 to 8 amino acids; the above drug complex wherein Y is p-phenylene group which may be substituted; the above drug complex wherein Y is unsubstituted p-phenylene group; the above drug complex wherein the polysaccharide derivative having carboxyl groups is a carboxy(C1-4)alkyldextran polyalcohol; the above drug complex wherein dextran polyalcohol that constitutes the carboxy(C-1-4)alkyldextran polyalcohol is dextran polyalcohol which is obtained by treating dextran under conditions that enable substantially complete polyalcoholization; the above drug complex wherein the carboxy(C1-4)alkyldextran polyalcohol is carboxymethyldextran polyalcohol; the above drug complex wherein the drug compound is an antineoplastic agent or an anti-inflammatory agent; the above drug complex wherein A-Rxe2x80x94NHxe2x80x94Yxe2x80x94CH2Oxe2x80x94COxe2x80x94 and an amino group of the drug compound are bound to each other; and the above drug complex wherein the drug compound is (1S,9S) 1-amino-9-ethyl-5-fluoro 2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo[de]pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-(9H,15H)-dione.